Palladium® complexes total synthesis reactions

The total synthesis of palytoxin (1) is a landmark scientific achievement. It not only extended the frontiers of target-oriented synthesis in terms of the size and complexity of the molecules, but also led to new discoveries and developments in the areas of synthetic methodology and conformational analysis. Among the most useful synthetic developments to emerge from this synthesis include the refinement of the NiCh/CrC -mediated coupling reaction between iodoolefins and aldehydes, the improvements and modifications of Suzuki s palladium-catalyzed diene synthesis, and the synthesis of A-acyl vinylogous ureas. 

The arylamine 780b required for the total synthesis of carbazomycin B (261) was obtained by catalytic hydrogenation, using 10% palladium on activated carbon, of the nitroaryl derivative 784 which was obtained in six steps and 33% overall yield starting from 2,3-dimethylphenol 781 (see Scheme 5.85). Electrophilic substitution of the arylamine 780b with the iron-complex salt 602 provided the iron complex 787 in quantitative yield. The direct, one-pot transformation of the iron complex 787 to carbazomycin B 261 by an iron-mediated arylamine cyclization was unsuccessful, probably because the unprotected hydroxyarylamine moiety is too sensitive towards the oxidizing reaction conditions. However, the corresponding 0-acetyl derivative... 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

A domino total synthesis of spirotryprostatin B (2) and three of its isomers has been published by Overman and Rosen, who apply two sequential palladium-catalyzed reactions (one-pot) to assemble the two spiro-fused rings [10] (Scheme 3). This work again makes it clear that complex heterocyclic systems may represent a harder challenge to synthetic... 

Vinyl epoxides can also be used as substrates for formation of optically active allyl amines catalyzed by the same type of chiral palladium complexes as in Eq. (10). By reaction of simple vinyl epoxides with phthalimide as the nitrogen source in the presence of the chiral palladium complexes as the catalyst, very high ee (> 98 %) and regioselectivity (> 97 %) were obtained [26]. A variety of different applications of the use of the palladium-catalyzed approach for the formation of allyl amines and the use of this in total synthesis has been pursued by several research groups, and further details can be obtained in a review by Trost et al. [19d]. 

In general, the telomerization reaction is defined as the dimerization of two molecules of a 1,3-diene in the presence of an appropriate nucleophile HX to yield substituted octadienes [216,217]. This reaction allows us to assemble simple starting materials in a 100% atom efficiency [218] and to easily prepare useful intermediates in the total synthesis of natural products [219,220] and industrial precursors [221], In light of numerous studies, the mechanism of the palladium-catalyzed telomerization reaction is well understood [222,223]. It is accepted that one strongly bound and sterically hindered ligand on the metal center is desirable to generate highly active species, characteristics fulfilled by (NHC)-Pd(O) complexes. 

As in the case of quinolines, isoquinolines can be prepared by metal-mediated annotation processes. Reaction of t-butylimines of iodo-benzaldehydes with acetylenes in the presence of palladium catalyst affords 3,4-disubstituted isoquinolines. The power of this reaction relies on its ability to introduce different type of substituents on 4-position of the heterocycle by using the formed intermediate palladium complex in the cross-coupling reaction with aryl and alkyl halides or alkenes. This methodology was successfully applied to the total synthesis of decumbenine... 

Corey and coworkers [45] later described the application of this reaction in the total synthesis of okaramine N (Scheme 9.16). Bisindole 110 was oxidatively cyclized using stoichiometric Pd(OAc)2 to form compound 111 in 38% yield. Although the yield was modest, the dihydroindoloazocine product could be elaborated in just two steps to afford okaramine N. This remarkably rapid synthesis highlights the efficacy of the palladium(II)-mediated oxidative Heck reaction to construct complex ring systems that can immediately expedite natural product synthesis. 

The total synthesis of (+)-linoxepin 76 was completed by use of a Eleck reaction to form the oxepine ring in the last step (13AGE5305). Notably, a palladium-catalyzed Catellani reaction was used to prepare precursor 74 and this is the first time that this reaction has been used in the synthesis of a complex natural product. 

In the total synthesis of the marine terpenoid (-)-frondosin B, Trauner and Hughes described an intramolecular palladium-catalyzed alkenylation reaction between a benzofuran and an enol triflate (124 to 125, Scheme 10.41). Although the mechanism to form the key seven-membered ring is still unclear, a reasonable hypothesis would involve oxidative addition of palladium(0) to the C—OTf bond, C3-palladation of the benzofuran and reductive elimination to form the new C—C bond. This work is notable as it was the first example of heteroaromatic C—H activation in a complex molecule setting. 

In the twentieth century, palladium was the most important metal catalyst in transition metal-catalyzed organic transformations. First, many types of transformations can be catalyzed by a palladium catalyst, including the Heck reaction, the cross-coupling reaction, and the Tsuji-Trost reaction. Second, palladium is extraordinarily tolerant of nearly any type of organic functional group and its high chemoselectivity makes it feasible for use in functionalized or complex systems. Due to these characteristics, palladium is an ideal catalyst in cascade reactions and the total synthesis of natural products. 

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